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The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO

Wink, David A., Feelisch, Martin, Fukuto, Jon, Chistodoulou, Danae, Jourd'heuil, David, Grisham, Matthew B., Vodovotz, Yoram, Cook, John A., Krishna, Murali, DeGraff, William G., Kim, SungMee, Gamson, Janet and Mitchell, James B. (1998) The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO Archives of Biochemistry and Biophysics, 351, (1), pp. 66-74. (doi:10.1006/abbi.1997.0565). (PMID:9501920).

Record type: Article


In addition to the broad repertoire of regulatory functions nitric oxide (NO) serves in mammalian physiology, the L-arginine:NO pathway is also involved in numerous pathophysiological mechanisms. While NO itself may actually protect cells from the toxicity of reactive oxygen radicals in some cases, it has been suggested that reactive nitrogen oxide species formed from nitric oxide synthase (NOS) can be cytotoxic. In addition to NO, the one electron reduction product NO- has been proposed to be formed from NOS. We investigated the potential cytotoxic role of nitroxyl (NO-), using the nitroxyl donor Angelis's salt, (AS; sodium trioxodinitrate, Na2N2O3) as the source of NO-. As was found to be cytotoxic to Chinese hamster V79 lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-(CN6)3-), which converts NO- to NO, afforded dramatic protection against AS-mediated cytotoxicity. Treatment of V79 cells with L-buthionine sulfoximine to reduce intracellular glutathione markedly enhanced AS cytotoxicity, which suggests that GSH is critical for cellular protection against the toxicity of NO-. Further experiments showed that low molecular weight transition metal complexes associated with the formation of reactive oxygen species are not involved in AS-mediated cytotoxicity since metal chelators had no effect. However, under aerobic conditions, AS was more toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA double strand breaks in whole cells, and this effect was completely prevented by coincubation of cells with ferricyanide or Tempol. The data in this study suggest that nitroxyl may contribute to the cytotoxicity associated with an enhanced expression of the L-arginine:NO pathway under different biological conditions.

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Published date: 1 March 1998
Organisations: Clinical & Experimental Sciences


Local EPrints ID: 337888
ISSN: 0003-9861
PURE UUID: da649776-6afa-426c-8a4d-e640a8761bc5
ORCID for Martin Feelisch: ORCID iD

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Date deposited: 29 Jun 2012 13:18
Last modified: 18 Jul 2017 06:00

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Author: David A. Wink
Author: Martin Feelisch ORCID iD
Author: Jon Fukuto
Author: Danae Chistodoulou
Author: David Jourd'heuil
Author: Matthew B. Grisham
Author: Yoram Vodovotz
Author: John A. Cook
Author: Murali Krishna
Author: William G. DeGraff
Author: SungMee Kim
Author: Janet Gamson
Author: James B. Mitchell

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